Premium
Comprehensive Analysis of Binding Sites in Tubulin
Author(s) -
Mühlethaler Tobias,
Gioia Dario,
Prota Andrea E.,
Sharpe May E.,
Cavalli Andrea,
Steinmetz Michel O.
Publication year - 2021
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202100273
Subject(s) - tubulin , allosteric regulation , computational biology , small molecule , binding site , chemistry , microtubule , ligand (biochemistry) , biology , plasma protein binding , biophysics , microbiology and biotechnology , biochemistry , receptor
Tubulin plays essential roles in vital cellular activities and is the target of a wide range of proteins and ligands. Here, using a combined computational and crystallographic fragment screening approach, we addressed the question of how many binding sites exist in tubulin. We identified 27 distinct sites, of which 11 have not been described previously, and analyzed their relationship to known tubulin–protein and tubulin–ligand interactions. We further observed an intricate pocket communication network and identified 56 chemically diverse fragments that bound to 10 distinct tubulin sites. Our results offer a unique structural basis for the development of novel small molecules for use as tubulin modulators in basic research applications or as drugs. Furthermore, our method lays down a framework that may help to discover new pockets in other pharmaceutically important targets and characterize them in terms of chemical tractability and allosteric modulation.